Mitochondrial Permeability Transitionin Aging Muscle

衰老肌肉中的线粒体渗透性转变

• 批准号: 10426409
• 负责人: Russell T Hepple
• 金额: $ 31.26万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10426409
• 关键词: Address; Aging; Atrophic; Attenuated; Autophagocytosis; Biological; Biopsy; CASP3 gene; Cardiac; Cell Culture Techniques; Cell Death; Cells; Cessation of life; Cholinergic Receptors; Clinical; Clinical Research; Consequentialism; Cytoplasm; Data; Data Set; Denervation; Elderly; Elderly man; Elderly woman; Exhibits; Fiber; Foundations; Genes; Goals; Grant; Grouping; Histology; Human; Impairment; Individual; Inner mitochondrial membrane; Ligase; Link; Membrane Potentials; Mitochondria; Mitochondrial Proteins; Mitochondrial Swelling; Modeling; Mus; Muscle; Muscle Cells; Muscle Fibers; Muscular Atrophy; Muscular Dystrophies; Nerve Degeneration; Neural Cell Adhesion Molecules; Neuromuscular Junction; Outcome; Outer Mitochondrial Membrane; Participant; Pathologic; Permeability; Phenotype; Property; Proteins; RNA; Rattus; Reactive Oxygen Species; Recording of previous events; Reperfusion Injury; Respiration Disorders; Rodent; Rodent Model; Role; Rupture; Signal Pathway; Skeletal Muscle; Testing; Time; Woman; aged; apoptosis inducing factor; bench to bedside; clinical translation; cytochrome c; cytokine; design; disability; effective therapy; endonuclease G; frailty; genetic approach; histological specimens; knock-down; men; mitochondrial membrane; mortality; muscle aging; muscle form; muscle strength; novel; novel therapeutic intervention; preservation; prevent; pro-apoptotic protein; recruit; transcription factor; walking speed; young adult

Project Summary/Abstract Mitochondrial permeability transition (MPT) involves the formation of a non-specific pore across the mitochondrial inner membrane that allows the passage of pro-apoptotic proteins and induces a large burst in reactive oxygen species (ROS). Whilst the pathological role of MPT in ischemia-reperfusion injury, cardiac aging, muscular dystrophy and neurodegeneration is well-established, the role of MPT in aging skeletal muscle has not been resolved. Our preliminary data in human and rodent muscle cell cultures identify MPT as a novel mechanism of muscle atrophy that can be blocked by interfering with proteins that regulate MPT, knocking down caspase 3, or by quenching mitochondrial ROS. Furthermore, we show that mitochondria have a lower threshold for inducing MPT in aging muscle, that there is an increased occurrence of MPT in aging human skeletal muscle, and that it only occurs in muscles that atrophy with aging, Finally, we also show in aged muscles that muscle fibers with mitochondria undergoing MPT are severely atrophied relative to normal muscle fibers and that they exhibit features suggesting they are denervated. On this basis, the first goal of this project is to address the fundamental mechanisms linking MPT to muscle atrophy using cell culture models. Secondly, using rat models we will manipulate the Ca2+ threshold for MPT to test the necessity and sufficiency of MPT for generating aging muscle phenotypes. Finally, we will leverage the powerful clinical dataset, deep muscle phenotyping, and availability of muscle histology blocks from the Study of Muscle Mobility and Aging (SOMMA) that will study 875 elderly men and women (³70 y), to establish the translational relevance of MPT for important clinical outcomes in elderly humans. By doing so, our studies will lay the foundation necessary to judge the merits of developing novel therapeutic approaches to prevent sensitization of mitochondria to MPT as a means of preserving muscle mass and mobility in advanced age.

项目摘要/摘要 线粒体通透性转变（MPT）涉及在线粒体上形成非特异性孔 内膜允许促凋亡蛋白的通过，并诱导反应性氧气大爆发 物种（ROS）。而MPT在缺血再灌注损伤，心脏衰老，肌肉的病理作用 营养不良和神经退行性成绩是良好的，MPT在衰老骨骼肌中的作用尚未是 解决。我们在人类和啮齿动物肌肉细胞培养物中的初步数据将MPT视为一种新的机制 可以通过干扰调节MPT，击倒caspase 3或 通过淬灭线粒体ROS。此外，我们表明线粒体的阈值较低 MPT在衰老的肌肉中，MPT在衰老的人类骨骼肌中的发生增加，并且 仅发生在衰老萎缩的肌肉中，最后，我们还显示出年龄的肌肉，肌肉纤维与 线粒体接受MPT相对于正常肌肉纤维严重萎缩，并且它们表现出 表明它们被取消的功能。在此基础上，该项目的第一个目标是解决基本 使用细胞培养模型将MPT与肌肉萎缩联系起来的机制。其次，使用大鼠模型我们将 操纵CA2+阈值以测试MPT产生衰老肌肉的必要和困难 表型。最后，我们将利用强大的临床数据集，深度肌肉表型以及可用性 肌肉组织学障碍肌肉流动性和衰老研究（SOMMA）将研究875个老年人 和妇女（“ 70 y）”，以建立MPT对较早的重要临床结果的转化相关性 人类。通过这样做，我们的研究将奠定必要的基础，以判断发展新颖的优点 防止线粒体对MPT的敏感性的治疗方法，以保存肌肉质量 和高龄的流动性。